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Tumor metastasis is a crucial impediment to the treatment of gastric cancer (GC), and the epithelial-to-mesenchymal transition (EMT) program plays a critical role for the initiation of GC metastasis. Thus, the aim of this study is to investigate the regulation of lnc-CTSLP4 in the EMT process during GC progression. We found that lnc-CTSLP4 was significantly downregulated in GC tumor tissues compared with adjacent non-tumor tissues, and its levels in GC tumor tissues were closely correlated with tumor local invasion, TNM stage, lymph node metastasis, and prognosis of GC patients. Loss- and gain-of-function assays indicated that lnc-CTSLP4 inhibited GC cell migration, invasion, and EMT in vitro, as well as peritoneal dissemination in vivo. Mechanistic analysis demonstrated that lnc-CTSLP4 could bind with Hsp90α/heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) complex and recruit E3-ubiquitin ligase ZFP91 to induce the degradation of HNRNPAB, thus suppressing the transcriptional activation of Snail and ultimately reversing EMT of GC cells. Taken together, our results suggest that lnc-CTSLP4 is significantly downregulated in GC tumor tissues and inhibits metastatic potential of GC cells by attenuating HNRNPAB-dependent Snail transcription via interacting with Hsp90α and recruiting E3 ubiquitin ligase ZFP91, which shows that lnc-CTSLP4 could serve as a prognostic biomarker and therapeutic target for metastatic GC., Graphical Abstract, lnc-CTSLP4 is significantly downregulated in GC tumor tissues and inhibits metastatic potential of GC cells by attenuating HNRNPAB-dependent Snail transcription via interacting with Hsp90α and recruiting E3-ubiquitin ligase ZFP91, which shows that lnc-CTSLP4 could serve as a prognostic biomarker and therapeutic target for metastatic GC.

Acquired resistance to tyrosine kinase inhibitors (TKIs) is the major obstacle to improve clinical efficacy in cancer patients. The epithelial-stromal interaction in tumor microenvironment influences cancer drug response to TKIs. Anlotinib is a novel oral multi-targeted TKI, and has recently been proven to be effective and safe for several tumors. However, if and how the epithelial-stromal interaction in tumor microenvironment affects anlotinib response in gastric cancer (GC) is not known. In this study, we found that anlotinib inhibited GC cells growth by inducing GC cells apoptosis and G2/M phase arrest in a dose- and time-dependent manner. Reactive oxygen species (ROS) mediated anlotinib-induced apoptosis in GC cells, while cancer-associated fibroblasts (CAFs) significantly suppressed anlotinib-induced apoptosis and ROS in GC cells. Increased BDNF that was derived from CAFs activated TrkB-Nrf2 signaling in GC cells, and reduced GC cells response to anlotinib. We identified secreted lactate from GC cells as the key molecule instructing CAFs to produce BDNF in a NF-κB-dependent manner. Additionally, functional targeting BDNF-TrkB pathway with neutralizing antibodies against BDNF and TrkB increased the sensitivity of GC cells towards anlotinib in human patient-derived organoid (PDO) model. Taken together, these results characterize a critical role of the epithelial-stroma interaction mediated by the lactate/BDNF/TrkB signaling in GC anlotinib resistance, and provide a novel option to overcome drug resistance., Graphical abstract Image 1, Highlights • Anlotinib induced apoptosis through ROS accumulation. • CAFs drive acquired resistance of GC to anlotinib. • TrkB activation by CAFs-derived BDNF confer resistance to anlotinib-induced ROS. • GC cells-secreted lactate induced BDNF expression of CAFs through activating NF-κB. • Blocking BDNF and TrkB reversed CAFs-induced acquired resistance to anlotinib.

Gastric cancer (GC) is one of the most frequent malignant tumors worldwide and is associated with high invasiveness, high metastasis and poor prognosis. Cancer-associated fibroblasts (CAFs), residing around tumor cells in tumor stroma, are important modifiers of tumor initiation and progression. However, the molecular mechanisms by which CAF's modulate tumor development have yet not to be characterized in GC. Here we performed tissue assay analyses identifying that Lumican, an extracellular matrix protein, is highly expressed in human gastric CAFs and its expression is positively associated with depth of invasion, lymph node metastasis, TNM stage and poor survival rate of GC. Functional studies revealed that integrin β1-FAK signaling pathways mediate the promoting effect of Lumican on GC cell proliferation, migration and invasion in vitro. In accordance with these observations, in GC cells co-cultured with CAFs in which Lumican had been knocked down, decreased gastric tumor growth and metastasis in vivo was apparent. In summary, CAF-derived Lumican contributes to tumorigenesis and metastasis of GC by activating the integrin β1-FAK signaling pathway.

// Chenchen Wang 1, * , Quan Zhou 1, * , Xiaofeng Wang 1 , Xiongyan Wu 1 , Xuehua Chen 1 , Jianfang Li 1 , Zhenggang Zhu 1 , Bingya Liu 1 , Liping Su 1 1 Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Liping Su, e-mail: franesulp@hotmail.com Bingya Liu, e-mail: byliu@sjtu.edu.cn Keywords: TLR7, Treg cells, Immune suppression, Anti-tumor effect Received: October 08, 2014 Accepted: November 16, 2014 Published: December 15, 2014 ABSTRACT Treg-induced immunosuppression is now recognized as a key element in enabling tumors to escape immune-mediated destruction. Although topical TLR7 therapies such as imiquimod have been proved successful in the treatment of dermatological malignancy and a number of conditions beyond the FDA-approved indications, the mechanism behind the effect of TLR7 on effector T cell and Treg cell function in cancer immunosurveillance is still not well understood. Here, we found that Loxoribin, one of the TLR7 ligands, could inhibit tumor growth in xenograft models of colon cancer and lung cancer, and these anti-tumor effects of Loxoribin were mediated by promoting CD4 + T cell proliferation and reversing Treg-mediated suppression via dendritic cells (DCs). However, deprivation of IL-6 using a neutralizing antibody abrogated the ability of Loxoribin-treated DCs, which reversed the Treg cell-mediated suppression. Furthermore, adoptive transfer of Loxoribin-treated DCs inhibited the tumor growth in vivo . Thus, this study links TLR7 signaling to the functional control of effector T cells and Treg cells and identifies Loxoribin as a new therapeutic strategy in cancer treatment, which may offer new opportunities to improve the outcome of cancer immunotherapy.

Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the mechanisms underlying stromal fibroblast activation and their promotion of tumor growth remain largely unknown in gastric cancer. Here, we show that normal fibroblasts (NFs) from non-cancerous regions of gastric cancer exhibit the traits of CAFs when grown together with gastric cancer cells in vivo. Activation of NFs can be induced by co-culture with gastric cancer cells, while deprivation of hepatocyte growth factor (HGF) using a neutralizing antibody inhibits the activation of NFs. Moreover, we identify HGF as an important factor from CAFs that acts in a paracrine manner to promote tumorigenesis in vitro and in vivo. Taken together, these results suggest that HGF may play a pivotal role in the regulatory circuit between gastric cancer cells and stromal fibroblasts, and neutralization of HGF inhibits both activation and tumor-promoting properties of CAFs.

Gastric cancer (GC) is one of the most common types of cancer worldwide, and it involves extensive local tumour invasion, metastasis and poor prognosis. Understanding the mechanisms regulating the progression of GC is necessary for the development of effective therapeutic strategies. Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is an important regulator controlling gene activation and repression, which has been thought to be involved in tumorigenesis. However, the role of TBL1XR1 in human GC remains largely unknown. Here, we find that TBL1XR1 is aberrantly expressed in human GC tissues, and TBL1XR1 levels are highly correlated with local tumour invasion, late tumor, lymph node, metastasis (TNM) stage and poor prognosis. Knockdown of TBL1XR1 by shRNA inhibits GC cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) in vitro, as well as tumorigenesis and peritoneal metastasis in vivo, whereas overexpression of TBL1XR1 produces the opposite effects. These effects are mediated by activation of the ERK1/2 signalling pathway, and inhibition of this pathway with a specific ERK1/2 inhibitor (U0126) significantly impairs the tumour-promoting effects induced by TBL1XR1. Moreover, TBL1XR1 mediated ERK1/2 activation is dependent on the β-catenin/MMP7/EGFR signalling pathway. In conclusion, TBL1XR1 contributes to GC tumorigenesis and progression through the activation of the β-catenin/MMP7/EGFR/ERK signalling pathway and may act as a new therapeutic target for GC.

// Xiaofeng Wang 1,* , Zhenjia Yu 1,* , Quan Zhou 1 , Xiongyan Wu 1 , Xuehua Chen 1 , Jianfang Li 1 , Zhenggang Zhu 1 , Bingya Liu 1 and Liping Su 1 1 Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Liping Su, email: // Keywords : TG2, gastric cancer, ERK1/2, tumor progression Received : August 26, 2015 Accepted : January 04, 2016 Published : January 11, 2016 Abstract Gastric cancer (GC) is one of the most common tumors worldwide and involves extensive local tumor invasion, metastasis, and poor prognosis. Understanding mechanisms regulating progression of GC is necessary for developing effective therapeutic strategies. Tissue transglutaminase-2 (TG2), a multifunctional member of the transglutaminase family, has been shown to be critical for tumor initiation and progression. However, how TG2 promotes the progression of GC is unknown. We report that TG2 was highly expressed in GC tissues and positively associated with depth of tumor invasion and late TNM stage. With gain- and loss-of-function approaches, we observed that TG2 promoted GC cell proliferation, migration, invasion, as well as tumorigenesis and peritoneal metastasis in vivo . These events were associated with the ERK1/2 pathway activation and an ERK1/2 inhibitor (U0126) inhibited cell proliferation, migration, and invasion induced by overexpression of TG2. In summary, TG2 contributes to tumorigenesis and progression of GC by activating the ERK1/2 signaling pathway and is a potential therapeutic target of metastatic gastric cancer.

Paired box gene 4 (PAX4) is a transcriptional modulator located on chromosome 7q32, and its expression is dysregulated in a variety of human cancers, suggesting that PAX4 may be important in multiple tumors as a driver gene. Here, we show that PAX4 promoted migration and invasion in human epithelial cancers by decreasing miR-144 and miR-451 (miR-144/451) expression levels. Accordingly, miR-144/451 suppressed the migratory and invasive phenotypes, even in PAX4-expressing cells. Mechanistically, miR-144/451 inhibits cancer metastasis by targeting the A disintegrin and metalloproteinase (ADAM) protein family members ADAMTS5 and ADAM10. Their dysregulation is associated with increased tumor invasiveness and metastasis, then reduced patient prognosis in certain epithelial cancers. This discovery suggests that a PAX4-miR-144/451-ADAMs axis regulates human epithelial cancer metastasis, thus opening up therapeutic possibilities and predicting prognosis for those cancer types.

Gastric cancer is one of the most common tumors worldwide with extensive local tumor invasion, metastasis and poor prognosis. Thus, understanding the mechanisms regulating progression of gastric cancer is the key for developing effective therapeutic strategies. Tissue tranglutaminase-2 (TG2), a multifunctional member of the transglutaminase (TGase) family, has already been proved to play an important role in tumor initiation and progression. However, the specific role and underlying molecular mechanisms of TG2 in the progression of gastric cancer (GC) remain unknown. Here we showed that TG2 was highly expressed in GC tissues and positively associated with depth of tumor invasion and late TNM stage. With gain and lose-of function approaches, we found that TG2 promotes GC cell proliferation, migration and invasion, as well as tumorigenesis and peritoneal metastasis in vivo. These events were associated with activating of ERK1/2 pathway, and ERK1/2 inhibitor U0126 inhibited cell proliferation, migration and invasion induced by overexpression of TG2. Taken together, these findings suggest that TG2 contributes to tumorigenesis and progression of GC by activating the ERK1/2 signaling pathway and is a potential therapeutic target of metastatic gastric cancer. Citation Format: Liping Su, Xiaofeng Wang, Quan Zhou, Xiongyan Wu, Bingya Liu. Tissue tranglutaminase-2 promotes gastric cancer progression via ERK1/2 pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 945.

Background: Cancer-associated fibroblasts (CAFs) are important modifiers of tumor progression, which can actively communicate with cancer cells through soluble factors. Interleukin-33 (IL-33) is a regulator of immune and inflammatory responses and has also been associated with certain epithelial tumors. Although the importance of CAFs in gastric cancer has been documented in experimental studies, the mechanisms by which CAFs and IL-33 promote gastric cancer remain unclear. Objectives: The aim of this study was to determine the role of IL-33 in the epithelial-stromal interaction in gastric cancer and if CAFs can promote the invasion of gastric cancer cells via ERK pathway through IL-33. Methods: CAFs and normal fibroblasts (NFs) were isolated from gastric cancer tissues and adjacent non-cancerous tissues respectively. The identification of CAFs was detected by immunofluorescence (IF) and qRT-PCR. IL-33 expression in CAFs and gastric cancer cells was detected by qRT-PCR. CAFs was co-cultured with gastric cancer cells in the presence of exogenous TNF-α, IL-1β and/or their corresponding neutralizing antibodies, the expression of IL-33 in CAFs was detected using qRT-PCR. EMT changes and activation of ERK pathway in gastric cancer cells after co-cultured with CAF-conditioned media were detected by qRT-PCR and western blot, and cell invasion assays were performed by using 8 μm transwell chambers. Results: Gastric CAFs expressed more α-SMA, a marker of myofibroblasts, and more fibroblast activation protein (FAP) when compared with patient-matched NFs. In comparison to gastric cancer cells and NFs, IL-33 was highly expressed in CAFs. Upregulation of IL-33 in CAFs can be induced by co-culture with gastric cancer cells or in the presence of TNF-α and IL-1β, while deprivation of TNF-α and IL-1β using their neutralizing antibodies inhibited the upregulation of IL-33. CAFs induced EMT changes of gastric cancer cells, which was demonstrated by decreased expression of E-cadherin and increased expression of Twist1, MMP2, ZEB1 and ZEB2. However, deprivation of IL-33 using a neutralizing antibody impaired the EMT changes of gastric cancer cells. Gastric cancer cells co-cultured with CAFs or CAFs conditioned media showed enhanced ability of invasion than gastric cancer cells alone. However, adding neutralizing IL-33 antibody or IL-33-siRNA-CAFs conditioned media or U0126 into the culture system led to significantly decreased invasion (P < 0.05) of gastric cancer cells. Moreover, IL-33 secreted from CAFs activated ERK pathway in gastric cancer cells, however, the invasion of gastric cancer cells was attenuated when IL-33-ERK pathway was blocked. Conclusions: TNF-α and IL-1β derived from gastric cancer cells can significantly enhance the expression of IL-33 in CAFs, and IL-33 secreted by CAFs promotes gastric cancer invasion via the ERK signaling pathway. Note: This abstract was not presented at the meeting. Citation Format: Liping Su, Quan Zhou, Chenchen Wang, Xiongyan Wu, Xiaofeng Wang, Jianfang Li, Zhenggang Zhu, Bingya Liu. IL-33 secreted by cancer-associated fibroblasts mediates epithelial-stromal interactions and promotes gastric cancer invasion via ERK signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5069. doi:10.1158/1538-7445.AM2015-5069

Objectives: The molecular mechanisms involved in the regulation of gastric cancer progression by CAFs are still unclear. The aim of the present study was to determine if CAFs can enhance the tumor epithelial-to-mesenchymal transition (EMT) and invasion of gastric cancer cells, and link CAFs with activation of the IL-6/JAK/ STAT3 signaling pathway in the progression of gastric cancer. Methods: Fibroblasts were isolated from gastric cancer. The identification of CAFs was defined by immunofluorescence staining and qRT-PCR. IL-6 expression in CAFs and gastric cancer cells was detected by qRT-PCR and ELISA. EMT and activation of Stat3 pathway in gastric cancer cells were detected by realtime PCR and western blot. Cell invasion assays were performed by using 8 μm transwell chambers. Results: IL-6 expression in gastric cancer tissue was significantly higher than that in adjacent non-tumor tissue (3.450ng/g vs 2.665ng/g,P Conclusions: CAFs induced EMT and invasion of gastric cancer cells through activation of the IL-6/JAK/STAT3 pathway. Citation Format: Liping Su, Xiongyan Wu, Quan Zhou, Chenchen Wang, Bingya Liu. Cancer-associated fibroblast promotes gastric cancer invasion and epithelial-mesenchymal transition via the IL-6/JAK/STAT3 signaling pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4803. doi:10.1158/1538-7445.AM2014-4803